Normal today, cancer tomorrow
Researchers discover how cancer can develop overnight
Without warning cancer can arise from a single catastrophic chromosomal event involving tens to hundreds of breaks in the DNA that are haphazardly pieced back together, researchers reported in the January 7th issue of Cell.
"In most cancers, a handful of mutations are accumulated over time, gradually evolving into a more aggressive form," said linkurl:Peter Campbell,;http://www.sanger.ac.uk/research/faculty/pcampbell/ blood oncologist at the Wellcome Trust Sanger Institute and lead author of the study. But in some situations, he adds, cancer can come out of nowhere, leaving its victim little time for treatment.
"What is particularly exciting about this observation is that it points to a novel mechanism that affects the stability of the genome in a very localized way," said linkurl:Ronald DePinho,;http://www.hms.harvard.edu/dms/bbs/fac/depinho.html cancer geneticist at the Belfer Institute for Applied Cancer Science at Harvard University, who was not involved in the study. "This paper explains how cancer can form in a relatively short period of time."
Normally when a cell undergoes drastic damage like the shattering of its chromosomes, what researchers call chromothripsis, it dies from a failure to pass innate cell cycle checkpoints that monitor DNA damage during mitosis. Sometimes, however, the cell attempts to rescue itself even after multiple breaks in its double stranded DNA (dsDNA). Though in most cases the repairs probably result in changes that are detrimental to the cells ability to continue dividing, Campbell said, by random chance the hodgepodge of repairs can occasionally amplify cancer genes or delete cancer suppressor genes, instigating the once normal cells to begin dividing uncontrollably.
Campbell and his group used high-throughput sequencing techniques to study the patterns of DNA rearrangements in various cancers -- such as colon, lung, pancreatic, melanoma and bone -- and discovered that massive rearrangements of dsDNA can occur in localized areas, on chromosomes 9 and 13, for example, where important cancer genes are known to exist.
Partly due to the focal nature of the damage, the group argues it's highly unlikely that catastrophic rearrangements occur as separate, sequential events, the traditional view of how cancer forms, but rather as a single, cataclysmic affair. While the phenomenon seems to occur in only a small percentage of all cancers -- just two to three percent --the researchers argue it's actually a substantial amount of cases, given the prevalence of cancer. Furthermore, they estimate that chromosomal breakdowns may account for up to 25 percent of bone cancers.
However, the cause of the damage remains elusive, though "the fact that it occurs more often in bone cancers is a clue about the mechanism of the event," said DePinho. "There must be something fundamentally different about bone cells because they are more susceptible to such catastrophic events."
One possibility, the group speculates, is that the damage occurs as a result of ionizing radiation from sources like x-rays or nuclear disasters, which is known to cause dsDNA breaks. "It's tempting to speculate that the reason we see [the phenomenon] more in bone is because it's more affected by ionizing radiation" than other kinds of cells, said Campbell. "Some radionuclides preferentially home to bone and would therefore preferentially irradiate [it]."
Campbell and his team plan to test this theory by taking tumor samples from people that have been exposed to large amounts of radiation, such as during the Chernobyl nuclear power plant accident in the Ukraine or the atomic bombing of Nagasaki, Japan during World War II. Campbell said they also plan to induce the phenomenon in vitro using lasers, which can have the same localizing effect on DNA as they observed, to see if the massive rearrangements cause the increases in cancer directly.
"Understanding what mechanism is causing these catastrophic events would be an exciting area of future research," said DePinho.
P.J. Stephens et al., "Massive Genomic Rearrangement Acquired in Single Catastrophic Event during Cancer Developement," Cell, 144:27-40, 2011.
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[16th December 2009]